Back to EveryPatent.com
| United States Patent |
5,770,221
|
|
Nakamura
, et al.
|
June 23, 1998
|
Formulation for percutaneous administration for treating disturbance in
micturition
Abstract
A formulation for percutaneous administration for treating disturbance in
micturition, which comprises a medicine for treating disturbance in
micturition contained in an adhesive layer containing a low-molecular
weight polyisobutylene, a high-molecular weight polyisobutylene and an oil
as main bases is disclosed. A formulation for percutaneous administration
for treating disturbance in micturition, which comprises a medicine for
treating disturbance in micturition contained in an adhesive containing a
low-molecular weight polyisobutylene, a high-molecular weight
polyisobutylene, an oil and an styrene-isoprene-styrene block copolymer as
main bases is also disclosed. The formulation for percutaneous
administration for treating disturbance in micturition of the present
invention is excellent in stability against change with time, low
irritative to skin, and excellent in transdermal absorbability, by using
these specified base components.
| Inventors:
|
Nakamura; Katsuhiro (Tsukuba, JP);
Koga; Nobuyuki (Tsukuba, JP)
|
| Assignee:
|
Hisamitsu Pharmaceutical Co., Inc. (Saga, JP)
|
| Appl. No.:
|
737160 |
| Filed:
|
November 15, 1996 |
| PCT Filed:
|
May 18, 1995
|
| PCT NO:
|
PCT/JP95/00946
|
| 371 Date:
|
November 15, 1996
|
| 102(e) Date:
|
November 15, 1996
|
| PCT PUB.NO.:
|
WO95/31190 |
| PCT PUB. Date:
|
November 23, 1995 |
Foreign Application Priority Data
| Current U.S. Class: |
424/449; 424/448; 424/486; 514/772.4; 604/307 |
| Intern'l Class: |
A61K 009/70; A61K 047/32; A61M 037/00 |
| Field of Search: |
424/484,486,448,449
|
References Cited
U.S. Patent Documents
| 4262003 | Apr., 1981 | Urquhart et al. | 424/267.
|
| 4623346 | Nov., 1986 | von Bittera et al. | 424/449.
|
| 4793337 | Dec., 1988 | Freeman et al. | 128/156.
|
| 4938759 | Jul., 1990 | Enscore et al. | 424/449.
|
| 5059189 | Oct., 1991 | Cilento et al. | 424/449.
|
| 5411740 | May., 1995 | Lee et al.
| |
| 5480648 | Jan., 1996 | Wendel et al. | 424/449.
|
| 5503843 | Apr., 1996 | Santus et al.
| |
| 5508038 | Apr., 1996 | Wang et al. | 424/448.
|
| Foreign Patent Documents |
| 61-271219 | Jan., 1986 | JP.
| |
| 4-95023 | Mar., 1992 | JP.
| |
| 4-99720 | Mar., 1992 | JP.
| |
| 4273818 | Sep., 1992 | JP.
| |
| 4266821 | Sep., 1992 | JP.
| |
Primary Examiner: Webman; Edward J.
Attorney, Agent or Firm: Townsend & Banta
Claims
We claim:
1. A formulation without scopolamine for percutaneous administration for
treating disturbance in micturition, which comprises a medicine for
treating disturbance in micturition in an adhesive, said adhesive
containing a low-molecular weight polyisobutylene having a
viscosity-average molecular weight of from about 10,000 to 100,000, a
high-molecular weight polyisobutylene having a viscosity-average molecular
weight of from 500,000 to 2,500,000 and an oil as main bases.
2. The formulation without scopolamine for percutaneous administration for
treating disturbance in micturition of claim 1, which comprises, based on
the total amount of the adhesive, 0.01 to 50 parts by weight of the
medicine for treating disturbance in micturition, said adhesive containing
1 to 60 parts by weight of said low-molecular weight polyisobutylene, 0.1
to 40 parts by weight of said high-molecular weight polyisobutylene, an
oil, and 5 to 50 parts by weight of a styrene-isoprene-styrene block
copolymer as main bases.
3. The formulation without scopolamine for treating disturbance in
micturition according to claim 1, wherein said medicine for treating
disturbance in micturition is a medicine for treating urinary
incontinence, a medicine for treating difficulty of micturition, a
medicine for treating pollakisuria, or a medicine for treating pain on
micturition.
4. The formulation without scopolamine for treating disturbance in
micturition according to claim 1, wherein said medicine for treating
disturbance in micturition is a medicine for treating urinary
incontinence.
5. The formulation without scopolamine for treating disturbance in
micturition according to claim 1, wherein said oil is selected from the
group consisting of liquid paraffin having a viscosity of 5 to 100
mm.sup.2 /s, natural squalene, synthetic squalene, squalane, and mixtures
thereof.
6. The formulation without scopolamine for treating disturbance in
micturition according to claim 1, which further comprises a transdermal
enhancer.
7. A formulation without scopolamine for percutaneous administration for
treating disturbance in micturition according to claim 3, wherein the
medicine for treating urinary incontinence, difficulty of micturition,
pollakisuria, or pain on micturition is selected from the group consisting
of bethanechol, distigmine, prostaglandins (PGE.sub.1, PGE.sub.2,
PGF.sub.2 .alpha.), propanthelin, oxybutynin, terodiline, flavoxate,
propiverine, vamicamide, urapidil, tiropramide, alfuzosin, imipramine,
amitriptyne, ethylphenylephrine, ephedrine, phenoxybenzamine, prazosin,
bunazocin, diazepam, dantrolene, clenbuterol, terazosin, inaperisone,
terflavoxate, naftopidil, and a pharmaceutically acceptable salt thereof.
8. The formulation without scopolamine for percutaneous administration for
treating disturbance in micturition according to claim 1, wherein said
medicine is oxybutynin or a pharmaceutically acceptable salt thereof.
Description
TECHNICAL FIELD
The present invention relates to a formulation for percutaneous
administration for treating disturbance in micturition. More particularly,
the present invention relates to a formulation for percutaneous
administration effective for treating disturbance in micturition, such as
urinary incontinence, difficulty of micturition, pollakisuria, pain on
micturition and the like.
BACKGROUND ART
The disturbance in micturition is a generic term concerning the disorders
of micturition conduct, and it includes urinary incontinence, difficulty
of micturition, pollakisuria, pain on micturition and the like.
Among them, the urinary incontinence is a disorder of micturition which may
be occurred in any age groups, and it has been increasingly given
attention by the general public in recent years. In particular, the
incidence of urinary incontinence in aged people is very high, it has been
still increasing, and it becomes a big problem before the coming aged
people society. Moreover, without regard to whether aged or not, there are
very many women suffering from urinary incontinence, and thus it can not
be overlooked.
There have been many attempts to treat the disturbances in micturition such
as urinary incontinence, and many peroral-administration type medicine for
treating disturbance in micturition have already been on the market.
However, since the patients suffering from severe cerebrovascular disease
bringing disturbance in micturition or the patients after operations of
various tumors and the like, need times when they are bedridden, the
administrations of the peroral-type medicine which must be administered
every constant hours, are difficult in many cases.
On the other hand, in order to avoid the extreme decrease in
bioavailability due to the so-called "first-pass effect" of liver in the
case of the peroral administration of medicines, and in order to prevent
the increase in incidence of side-effects due to the temporary increase in
the concentration in blood, there have been many attempts to form various
medicines into formulation for percutaneous administration as a method for
slow-releasing medicines. The medicine for treating disturbance in
micturition is expected to be administered as a formulation for
percutaneous administration.
The Japanese Un-examined Patent Publication No.Hei 4-266821 describes that
the medicines for treating disturbance in micturition such as terodiline,
oxybutynin, propiverine, flavoxate are formed into percutaneous
absorption-type therapeutic formulations.
In addition, the Japanese Un-examined Patent Publication No.Hei 4-273818
describes that terodiline, oxybutynin and the like are formed into
percutaneous absorption-type therapeutic formulations such as patches and
solutions.
However, in these publications, the drug stability which is important in
forming formulations, and the physical stability, the irritativeness to
skin and the constant releasability of the formulations are not
sufficiently investigated. For example, although in Examples in the above
Japanese Un-examined Patent Publication No.Hei 4-266821, terodiline and
oxybutynin are used as hydrochlorides, and aqueous bases are prepared to
be investigated, a sufficient drug stability can not be expected due to
the mutual action of many additives and water contained in the
formulation. The number of times of application of drugs is expected to be
small, such as one time/day or one time/two days, by the above reasons and
the like. However, in the case of aqueous bases, the number of times of
application need to be large, because the adhesive stability at the time
of long period adhesion is poor.
Further, it is the same in the above Japanese Un-Examined Patent
Publication No.Hei 4-273718, the stability of drug and the irritativeness
to skin and the like of the formulation are poor, and it can not be deemed
that the formulation meets the requirements of commercialization.
Therefore, the purpose of the invention is to provide a formulation for
percutaneous administration for treating disturbance in micturition, which
can stably maintain a medicine for treating disturbance in micturition
being an active component, and by which the medicine may be percutaneously
absorbed constantly and efficiently and an excellent pharmaceutical effect
is exhibited.
The present inventors have researched earnestly, and as the results, they
found that the above-mentioned purpose may be attained by containing a
medicine for treating disturbance in micturition into an adhesive which
contains a low-molecular weight polyisobutylene, a high-molecular weight
polyisobutylene and an oil as main bases.
DISCLOSURE OF INVENTION
The present invention relates to a formulation for percutaneous
administration for treating disturbance in micturition, which comprises a
medicine for treating disturbance in micturition contained in an adhesive
containing a low-molecular weight polyisobutylene, a high-molecular weight
polyisobutylene and an oil as main bases.
The present invention also relates to the formulation for percutaneous
administration for treating disturbance in micturition, which comprises,
based on the total amount of the adhesive, 0.01 to 50 parts by weight of
the medicine for treating disturbance in micturition contained in the
adhesive containing 1 to 60 parts by weight of the low-molecular weight
polyisobutylene, 0.1 to 40 parts by weight of the high-molecular weight
polyisobutylene and 10 to 60 parts by weight of the oil as main bases.
The present invention also relates to a formulation for percutaneous
administration for treating disturbance in micturition, which comprises a
medicine for treating disturbance in micturition contained in an adhesive
containing a low-molecular weight polyisobutylene, a high-molecular weight
polyisobutylene, an oil and an styrene-isoprene-styrene block copolymer as
main bases.
The present invention also relates to the formulation for percutaneous
administration for treating disturbance in micturition, which comprises,
based on the total amount of the adhesive, 0.01 to 50 parts by weight of
the medicine for treating disturbance in micturition contained in the
adhesive containing 1 to 60 parts by weight of the low-molecular weight
polyisobutylene, 0.1 to 40 parts by weight of the high-molecular weight
polyisobutylene, 10 to 60 parts by weight of the oil and 5 to 50 parts by
weight of the styrene-isoprene-styrene block copolymer as main bases.
The present invention also relates to the formulation for percutaneous
administration for treating disturbance in micturition, wherein the
medicine for treating disturbance in micturition is a medicine for
treating urinary incontinence, a medicine for treating difficulty of
micturition, a medicine for treating pollakisuria, or a medicine for
treating pain on micturition.
The present invention also relates to the formulation for percutaneous
administration for treating disturbance in micturition, wherein the
medicine for treating disturbance in micturition is a medicine for
treating urinary incontinence.
The present invention also relates to the formulation for percutaneous
administration for treating disturbance in micturition, wherein the
viscosity-average molecular weight of the low-molecular weight
polyisobutylene is in the range from 10,000 to 100,000 and the
viscosity-average molecular weight of the high-molecular weight
polyisobutylene is in the range from 500,000 to 2,500,000.
The present invention also relates to the formulation for percutaneous
administration for treating disturbance in micturition, wherein the oil is
at least one selected from the group comprising liquid paraffin having a
viscosity of 5 to 100 mm.sup.2 /s, natural and synthetic squalene and
squalane.
The present invention also relates to the formulation for percutaneous
administration for treating disturbance in micturition, which further
comprises a transdermal absorption enhancer.
The present invention will be explained in detail.
The medicine for treating disturbance in micturition which is an active
component of the formulation for percutaneous administration for treating
disturbance in micturition, is not limited to, but may be classified into
the medicines for treating urinary incontinence, the medicines for
treating difficulty of micturition, the medicines for treating
pollakisuria or the medicines for treating pain on micturition.
The term "urinary incontinence" used in the invention means involuntary
defluxion of urine, and may include the overflow type incontinence which
is occurred when bladder is filled with urine anuretically and urine is
overflowed, the urgent type incontinence which is occurred for the reason
that the micturition can not be controlled when micturition is felt, the
stress type incontinence which is occurred only when the abdominal
pressure is increased, the true type incontinence which is occurred
continuously for the reason that the bladder is not filled with urine due
to the loss of function of sphincter muscle of urethra and the like.
The term "difficulty of micturition" means a condition when urine can not
easily voided, and may include the delay of starting of micturition, the
extension of micturition time, the impossibility of micturition without
applying abdominal pressure, the fining of ureter, the dropping of urine
at the end of micturition and the like.
The term "pollakisurea" means a increase of the number of micturition
times, and indicates the condition in which approximately 10 or more
times/day of micturition is occurred. When the pollakisurea becomes
severe, the micturition is not disappeared just after micturition and the
tenesmus is occurred. There is the nocturnal micturition in which two or
more micturitions are occurred during sleeping.
The term "pain on micturition" means a pain felt in urethra at the time of
micturition. The pain may felt only at the beginning or end of micturition
in some cases. In addition, there is a pain felt in bladder when bladder
is filled.
Further, the medicine for treating disturbance in micturition which is the
active component of the formulation for percutaneous administration for
treating disturbance in micturition of the present invention, can be
classified into 1) the medicines for promoting the contraction of
micturition muscle, 2) the medicines for inhibiting the contraction of
micturition muscle, 3) the medicines for promoting the tension of
sphincter muscle, and 4) the medicines for inhibiting the contraction of
sphincter muscle.
As the above 1) medicines for promoting the contraction of micturition
muscle, the cholinergic agents, the anticholinesterase agents, the
prostaglandins and the like may be exemplified. Further, as the above 2)
medicines for inhibiting the contraction of micturition muscle, the
anticholinergic agents, the smooth muscle relaxants, the tricyclic
antidepressants and the like may be exemplified. Further, as the above 3)
medicines for promoting the tension of sphincter muscle, the adrenergic
agents and the like may be exemplified. Further, as the above 4) medicines
for inhibiting the contraction of sphincter muscle, .alpha.-adrenoceptor
blockers, the skeletal muscle relaxants and the like may be exemplified.
As the concrete examples of the medicines for treating disturbance in
micturition, bethanechol, distigmine, prostaglandins (PGE.sub.1,
PGE.sub.2, PGF.sub.2 .alpha. et al), propanthelin, oxybutynin, terodiline,
flavoxate, propiverine, vamicamide, urapidil, tiropramide, alfuzosin,
imipramine, amitriptyne, ethylphenylephrine, ephedrine, phenoxybenzamine,
prazosin, bunazocin, diazepam, dantrolene, clenbuterol, terazosin,
inaperisone, terflavoxate, naftopidil and the like, or pharmaceutically
acceptable salts thereof may be exemplified. Among the pharmaceutically
acceptable salts, hydrochloride is particularly preferable.
The medicine for treating disturbance in micturition which is an active
component of the formulation for percutaneous administration for treating
disturbance in micturition, is desirably contained in the range from 0.01
to 50 parts by weight, preferably in the range from 0.1 to 30 parts by
weight, and more preferably in the range from 1 to 20 parts by weight,
based on the total amount of the adhesive. When the content of the
medicine is less than 0.01 parts by weight, the pharmaceutical effect of
the therapeutic medicine can not be expected sufficiently and the
continuous exhibition of the pharmaceutical effect can not be desired in
some cases. When the content exceeds 50 parts by weight, the adhesiveness
to skin of the base layer will tend to decrease and thus it is not
preferable.
The adhesive used in the formulation for percutaneous administration for
treating disturbance in micturition of the present invention, contains a
low-molecular weight polyisobutylene and a high-molecular weight
polyisobutylene and an oil as main bases. The formulation for percutaneous
administration for treating disturbance in micturition of the present
invention, is excellent in the performances as an adhesive such as
coagulation power and adhesion power, by containing the above three kinds
of main bases, and thus it can control the drug release efficiently.
The viscosity-average molecular weight of the low-molecular weight
polyisobutylene is preferably in the range from 10,000 to 100,000, and the
viscosity-average molecular weight of the high-molecular weight
polyisobutylene is preferably in the range from 500,000 to 2,500,000.
The oils are preferably selected from the group comprising liquid paraffin
having a viscosity of 5 to 100mm.sup.2 /s, natural and synthetic squalene
and squalane.
Squalene or Squalane is a safe hydrocarbon compound and used widely as a
cosmetic from the view point of its low irritativeness to skin, and it can
be used preferably in the formulation of the present invention.
The contents of the main bases are preferably determined in consideration
of the physical characteristics of the formulation as adhesive, such as
adhesiveness, coagulation power and drug releasability. Preferably, the
content of the low-molecular weight polyisobutylene is in the range from 1
to 60 parts by weight, particularly in the range from 20 to 50 parts by
weight, and the content of the high-molecular weight polyisobutylene is in
the range from 0.1 to 40 parts by weight, particularly in the range from
10 to 30 parts by weight, based on the total amount of the adhesive. If
the content of the low-molecular weight polyisobutylene is less than 1
parts by weight, adhesiveness is poor, and if it exceeds 60 parts by
weight, the coagulation power is poor and thus it is not preferable.
Further, if the content of the high-molecular weight polyisobutylene is
less than 0.1 parts by weight, the coagulation power is poor, and if it
exceeds 40 parts by weight, adhesiveness is poor and thus it is not
preferable.
The content of the oils is preferably in the range from 10 to 60 parts by
weight, more preferably in the range from 20 to 50 parts by weight based
on the total amount of the adhesive. By containing the oils, a decrease of
the irritativeness to skin and an improvement of the drug releasability
may be attained. However, if the content exceeds 60 parts by weight, the
coagulation power as a pharmaceutical formulation and the adhesiveness and
stability of the formulation, may be avoided in some cases. Further, if
the content of the oils is less than 10 parts by weight, the adhesion
power is deficient, and the sufficient adhesiveness can not be given, and
thus it is not preferable.
The adhesive used in the formulation for percutaneous administration for
treating disturbance in micturition of the present invention may further
contain styrene-isoprene-styrene block copolymer. By containing the
styrene-isoprene-styrene block copolymer, the coagulation power of the
adhesive is further improved, and the exudation and the like during
storage of the formulation can be prevented.
When the adhesive contains the styrene-isoprene-styrene block copolymer, in
consideration of the physical properties as the adhesive of the
formulation such as adhesiveness and coagulation power and the drug
releasability, based on the total amount of the adhesive, the adhesive
preferably contains 1 to 30 parts by weight, particularly 2 to 20 parts by
weight of low-molecular weight polyisobutylene, 0.1 to 20 parts by weight,
particularly 0.1 to 10 parts by weight of high-molecular weight
polyisobutylene, 5 to 50 parts by weight, particularly 10 to 40 parts by
weight of the styrene-isoprene-styrene block copolymer. The content of the
low-molecular weight polyisobutylene is less than 1 parts by weight, the
adhesiveness is poor, and if it exceeds 30 parts by weight, the
coagulation power is poor, and thus it is not preferable. In addition, the
content of the high-molecular weight polyisobutylene is less than 0.1
parts by weight, the coagulation power is poor, and if it exceeds 20 parts
by weight, the adhesiveness is poor, and thus it is not preferable.
Further, if the content of the styrene-isoprene-styrene block copolymer is
less than 5 parts by weight, the coagulation power is poor, and it exceeds
50 parts by weight, the drug releasability is poor, and thus it is not
preferable.
Moreover, the formulation for percutaneous administration for treating
disturbance in micturition of the present invention, may contain a
transdermal adsorption enhancer, if desired. The transdermal adsorption
enhancer which may be used in the present invention is not limited to, but
terpene oils such as l-menthol, peppermint oil and d-limonene, aliphatic
acid esters such as glyceryl monolaurate, glyceryl monooleate and diethyl
sebacate, azacycloalkanes such as Azon and 1-›2-(decyl
thio)ethyl!azacyclopentane-2-one, other oleic acid, lauric acid, myristic
acid, oleyl alcohol, 1-›2›(decyl thio)ethyl!azacyclopentane-2-one
(hereinafter it is abbreviated as "HPE-101") and the like may be
exemplified. One of more of these transdermal absorption enhancers are
contained in an amount of 15 parts by weight or less, preferably in the
range from 0.5 to 5 weight parts, based on the total amount of the
adhesive.
In addition, in the base of the adhesive of the present invention, a
tackifying resin, a solubilizer or a solution adjuvant, or a chemically
stable filler may be contained, if desired. By adding the tackifying resin
and filler, the constant releasability may be attained for a long time
period without deteriorating the adhesiveness and coagulation power of the
base.
As the tackifying resin which may be used in the present invention, the
resin which is in crystalline state and the softening point of which is in
the range from 50.degree. to 250.degree. C., is preferable. As the
concrete examples, rosin or its derivatives, terpene resin, terpene,
phenol resins, petroleum resin, alkyl-phenol resin, xylene resin and the
like may be exemplified. One or more of these resins may be preferably
contained in an amount 50 parts by weigh or less, particularly in the
range from 5 to 40 parts by weight, based on the total amount of the
formulation for percutaneous administration for treating disturbance in
micturition.
As the solubilizer or solution adjuvant, crotamiton, (poly)ethylene glycol,
(poly)propylene glycol and the like may be exemplified. One or more of the
solubilizers or solution adjuvants are preferably contained in an amount
of 10 parts by weight or less, particularly in the range from 0.1 to 5
parts by weight, based on the total amount of the formulation for
percutaneous administration for treating disturbance in micturition.
Further, as the fillers, chemically stable fillers are preferable, and
titanium oxide, zinc oxide, talc, silicic anhydride, magnesium silicate,
aluminum silicate, polyethylene beads, polystyrene beads, zinc stearate
and the like may be exemplified concretely. The particle diameter of the
filler is desirably 20 .mu.m or less, particularly in the range from 0.5
to 10 .mu.m. One or more of the fillers may be contained in an amount of
10 parts by weight or less, preferably in the range from 0.1 to 5 parts by
weight, based on the total amount of the formulation for percutaneous
administration for treating disturbance in micturition.
The formulation for percutaneous administration for treating disturbance in
micturition of the present invention, is preferably formed into a base
layer by applying the above adhesive onto the surface of a backing.
The backings which may be used in the formulation for percutaneous
administration for treating disturbance in micturition of the present
invention, are not limited to, but the backings having flexibility to the
extent that extreme unconformability is not produced when adhered to skin,
are preferable. For example, a single layer film comprising a plastic film
such as polyethylene, polypropylene, polyester, polyvinyl acetate,
ethylene-vinyl acetate copolymer, polyvinyl chloride and polyurethane, a
metal foil such as aluminum foil and tin foil, non-woven fabric, fabric,
or paper and the like, and laminated layers having the layers, may be
exemplified.
Further, in order to improve the sealability and adhesiveness of these
backings to the base layer, coroma discharge treatment, plasma treatment,
oxidation treatment and the like are desirably made on the base
layer-forming surface of the substrate.
The exposed surface of the base layer of the formulation for percutaneous
administration for treating disturbance in micturition of the present
invention, is desirably covered and protected with a release liner such as
paper, plastics and the like which had been release-treated by applying
silicone resin, fluorocarbon polymer and the like, by just before the
administration to skin.
The formulation for percutaneous administration for treating disturbance in
micturition of the present invention, is appropriately administered
percutaneously in an amount of 1 to 50 mg on the basis of the medicine for
treating disturbance in micturition, at an interval from once/a day to
once/two days, but it can be administered at an interval of one time/three
days.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the results of the transdermal absorption test using rats.
FIG. 2 shows the results of the transdermal absorption test using human
skin.
In FIGS. 1 and 2, .largecircle. shows the results of the formulation of the
following Example 1, .circle-solid. shows the formulation of the following
Example 2, .quadrature. shows the formulation of the following Example 3,
.box-solid. shows the formulation of the following example 4, .diamond.
shows the formulation of the following Example 5, X shows the formulation
of the following Example 6, shows the formulation of the following
Example 7, .diamond-solid. shows the formulation of the following
Comparative Example 1, .DELTA. shows the formulation of the following
Comparative Example 2, .quadrature. shows the formulation of the following
Comparative Example 3, .vertline. shows the formulation of the following
Comparative Example 4, shows the formulation of the following Comparative
Example 19, and shows the formulation of Comparative Example 20.
FIG. 3 shows the results of the evaluation test on the pharmaceutical
effects with the cystometry using rats.
EXAMPLES
The present invention will be explained in more detail with Examples,
hereinafter.
Example 1
______________________________________
High-molecular weight Polyisobutylene
15.5 parts by weight
(viscosity-average molecular weight: 1,110,000)
Low-molecular weight Polyisobutylene
16.5 parts by weight
(viscosity-average *molecular weight: 40,000)
Squalene 45.0 parts by weight
Hydrogenated rosin ester
10.0 parts by weight
Peppermint Oil 3.0 parts by weight
______________________________________
To a polyisobutylene solution obtained by dissolving a composition
containing the above components in hexane (total solids: 25.0 wt %),
oxybutynin was added and mixed so as to have an oxybutynin content of 10
parts by weight when dried. The obtained mixture was applied onto a
release liner so as to have a thickness of 50 .mu.m after drying, and
dried to form a base layer.
Then, the base layer thus obtained was laminated on a polyester film
(thickness: 25 .mu.m) to obtain a formulation for percutaneous
administration for treating disturbance in micturition of the present
invention.
Example 2
______________________________________
High-molecular weight Polyisobutylene
17.0 parts by weight
(viscosity-average molecular weight: 1,110,000)
Low-molecular weight Polyisobutylene
26.0 parts by weight
(viscosity-average molecular weight: 40,000)
Liquid paraffin 44.0 parts by weight
(Crystol (Registered Trademark) 352)
HPE-101 (1-›2-(decylthio)ethyl!azacyclopentane-
3.0 parts by weight
2-one: generic name:pirotiodecane)
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 1 except that the above composition containing the
above components was used.
Example 3
______________________________________
High-molecular weight Polyisobutylene
22.0 parts by weight
(viscosity-average molecular weight: 990,000)
Low-molecular weight Polyisobutylene
25.0 parts by weight
(viscosity-average molecular weight: 30,000)
Liquid paraffin 43.0 parts by weight
(Crystol (Registered Trademark ) 352)
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 1, except that the above composition containing the
above components was used and that oxybutynin hydrochloride was used in
place of oxybutynin.
Example 4
______________________________________
High-molecular weight Polyisobutylene
2.0 parts by weight
(viscosity-average molecular weight: 1,100,000)
Low-molecular weight Polyisobutylene
7.0 parts by weight
(viscosity-average molecular weight: 40,000)
Styrene-isoprene-styrene Block copolymer
1.0 parts by weight
Liquid paraffin 34.0 parts by weight
(Crystol (Registered Trademark) 352)
Hydrogenated rosin ester
27.0 parts by weight
HPE-101 (1-›2-(decylthio)ethyl!-
3.0 parts by weight
azacyclopentane-2-one:
generic name: pirotiodecane)
Antioxidant 1.0 parts by weight
______________________________________
Oxybutynin was added to the composition containing the above components so
as to have an oxybutynin content of 10 weight parts. The mixture was
heated up to 180.degree. C. under nitrogen flow, and mixed and stirred.
After stirring for two hours, the obtained mixture was applied on a
release liner so as to have a thickness of 50 .mu.m to form a base layer.
Then, the base layer thus obtained was laminated on a polyester film
(thickness: 25 .mu.m) to form a formulation for percutaneous
administration for treating disturbance in micturition of the present
invention.
Example 5
______________________________________
High-molecular weight Polyisobutylene
1.5 parts by weight
(viscosity-average molecular weight: 1,600,000)
Low-molecular weight Polyisobutylene
6.5 parts by weight
(viscosity-average molecular weight: 30,000)
Styrene-isoprene-styrene Block copolymer
13.0 parts by weight
Liquid paraffin 30.0 parts by weight
(Crystol (Registered Trademark) 352)
Liquid paraffin 7.0 parts by weight
(Crystol (Registered Trademark) 52)
Hydrogenated rosin ester
26.0 parts by weight
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 3, except that the above composition containing the
above components was used and that oxybutynin was used so as to have a
content of 15 parts by weight in place of oxybutynin hydrochloride.
Example 6
______________________________________
High-molecular weight Polyisobutylene
2.6 parts by weight
(viscosity-average molecular weight: 1,110,000)
Low-molecular weight Polyisobutylene
10.2 parts by weight
(viscosity-average molecular weight: 40,000)
Styrene-isoprene-styrene Block copolymer
20.0 parts by weight
Liquid paraffin 21.0 parts by weight
Hydrogenated rosin ester
35.2 parts by weight
Crotamiton 5.0 parts by weight
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 4, except that the above composition containing the
above components was used and that oxybutynin was used so as to have a
content of 5 parts by weight in place of oxybutynin hydrochloride.
Example 7
______________________________________
High-molecular weight Polyisobutylene
2.4 parts by weight
(viscosity-average molecular weight: 1,600,000)
Low-molecular weight polyisobutylene
9.7 parts by weight
(viscosity-average molecular weight: 30,000)
styrene-isoprene-styrene Block copolymer
18.1 parts by weight
Liquid paraffin 19.8 parts by weight
Hydrogenated rosin ester
34.0 parts by weight
Crotamiton 5.0 parts by weight
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 4, except that the above composition containing the
above components was used and that oxybutynin was used so as to have a
content of 10 parts by weight in place of oxybutynin hydrochloride.
Example 8
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 1, except that vamicamide was used in place of
oxybutynin.
Example 9
______________________________________
High-molecular weight Polyisobutylene
1.0 parts by weight
(viscosity-average molecular weight: 900,000)
Low-molecular weight Polyisobutylene
16.0 parts by weight
(viscosity-average molecular weight: 55,000)
Styrene-isoprene-styrene Block copolymer
20.0 parts by weight
Squalene 26.0 parts by weight
Hydrogenated rosin ester
6.0 parts by weight
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 3, except that the above composition containing the
above components was used and that vamicamide was used so as to have a
content of 30 parts by weight in place of oxybutynin hydrochloride.
Example 10
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 1, except that naftopidil was used in place of
oxybutynin.
Example 11
______________________________________
High-molecular weight Polyisobutylene
2.0 parts by weight
(viscosity-average molecular weight: 1,900,000)
Low-molecular weight Polyisobutylene
10.0 parts by weight
(viscosity-average molecular weight: 40,000)
Styrene-isoprene-styrene Block copolymer
8.0 parts by weight
Liquid paraffin 28.0 parts by weight
(Crystol (Registered Trademark) 352)
Hydrogenated rosin ester
18.0 parts by weight
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 3, except that the above composition containing the
above components was used and that naftopidil was used so as to have a
content of 35 parts by weight in place of oxybutynin hydrochloride.
Example 12
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 2, except that prazosin was used in place of
oxybutynin.
Example 13
______________________________________
High-molecular weight Polyisobutylene
1.0 parts by weight
(viscosity-average molecular weight: 900,000)
Low-molecular weight Polyisobutylene
22.0 parts by weight
(viscosity-average molecular weight: 15,000)
Styrene-Isoprene-styrene Block copolymer
13.0 parts by weight
Liquid paraffin 15.0 parts by weight
(Crystol (Registered Trademark) 352)
Hydrogenated rosin ester
15.0 parts by weight
HPE-101 (1-›2-(decylthio)ethyl!
3.0 parts by weight
azacyclopentane-2-one:
generic name: pirotiodecane)
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 3, except that the above composition containing the
above components was used and that prazosin was used so as to have a
content of 30 parts by weight in place of oxybutynin hydrochloride.
Example 14
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 3, except that bunazocin was used in place of
oxybutynin hydrochloride.
Example 15
______________________________________
High-molecular weight Polyisobutylene
34.0 parts by weight
(viscosity-average molecular weight: 600,000)
Low-molecular weight Polyisobutylene
15.0 parts by weight
(viscosity-average molecular weight: 80,000)
Liquid paraffin 18.0 parts by weight
(Crystol (Registered Trademark) 352)
Peppermint oil 3.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 1, except that the above composition containing the
above components was used and that bunazocin was used so as to have a
content of 35 parts by weight in place of oxybutynin.
Example 16
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 4, except that terazosin was used in place of
oxybutynin.
Example 17
______________________________________
High-molecular weight Polyisobutylene
12.0 parts by weight
(viscosity-average molecular weight: 1,110,000)
Low-molecular weight Polyisobutylene
50.0 parts by weight
(viscosity-average molecular weight: 80,000)
Liquid paraffin 7.0 parts by weight
(Crystol (Registered Trademark) 352)
Hydrogenated rosin ester
8.0 parts by weight
Peppermint oil 3.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 1, except that the above composition containing the
above components was used and that terazosin was used so as to have a
content of 20 parts by weight in place of oxybutynin.
Example 18
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 4, except that terodiline hydrochloride was used in
place of oxybutynin.
Example 19
______________________________________
High-molecular weight Polyisobutylene
12.0 parts by weight
(viscosity-average molecular weight: 1,900,000)
Low-molecular weight Polyisobutylene
20.0 parts by weight
(viscosity-average molecular weight: 15,000)
Liquid paraffin 20.0 parts by weight
(Crystol (Registered Trademark) 352)
Peppermint Oil 3.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 1, except that the above composition containing the
above components was used and that terodiline hydrochloride was used so as
to have a content of 45 parts by weight in place of oxybutynin.
Example 20
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 4, except that inaperisone was used in place of
oxybutynin.
Example 21
______________________________________
High-molecular weight Polyisobutylene
1.0 parts by weight
(viscosity-average molecular weight: 900,000)
Low-molecular weight Polyisobutylene
8.0 parts by weight
(viscosity-average molecular weight: 40,000)
Styrene-isoprene-styrene Block copolymer
40.0 parts by weight
Liquid paraffin 10.0 parts by weight
(Crystol (Registered Trademark) 352)
Hydrogenated rosin ester
10.0 parts by weight
HPE-101 (1›2-(decylthio)ethyl!-
5.0 parts by weight
azacyclopentane-2-one:
generic name: pirotiodecane)
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 3, except that the above composition containing the
above components was used and that inaperisone was used so as to have a
content of 25 parts by weight in place of oxybutynin hydrochloride.
Example 22
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 5, except that propiverine was used in place of
oxybutynin.
Example 23
______________________________________
High-molecular weight Polyisobutylene
15.0 parts by weight
(viscosity-average molecular weight: 600,000)
Low-molecular weight Polyisobutylene
12.0 parts by weight
(viscosity-average molecular weight: 40,000)
Styrene-isoprene-styrene Block copolymer
20.0 parts by weight
Liquid paraffin 22.0 parts by weight
(Crystol (Registered Trademark) 352)
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 3, except that the above composition containing the
above components was used and that propiverine was used so as to have a
content of 30 parts by weight in place of oxybutynin hydrochloride.
Example 24
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 5, except that tamsulosin was used in place of
oxybutynin.
Example 25
______________________________________
High-molecular weight Polyisobutylene
2.0 parts by weight
(viscosity-average molecular weight: 1,110,000)
Low-molecular weight Polyisobutylene
8.0 parts by weight
(viscosity-average molecular weight: 90,000)
Styrene-isoprene-styrene Block copolymer
19.0 parts by weight
Liquid paraffin 24.0 parts by weight
(Crystol (Registered Trademark)352)
Hydrogenated rosin ester
21.0 parts by weight
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition of the present invention was obtained in the same manner as
described in Example 3, except that the above composition containing the
above components was used and that tamusulosin was used so as to have a
content of 25 parts by weight in place of oxybutynin hydrochloride.
Example 26
______________________________________
High-molecular weight Polyisobutylene
1.0 parts by weight
(viscosity-average molecular weight: 2,200,000)
Low-molecular weight Polyisobutylene
7.0 parts by weight
(viscosity-average molecular weight: 30,000)
Styrene-isoprene-styrene Block copolymer
18.0 parts by weight
Liquid paraffin 39.0 parts by weight
(Crystol (Registered Trademark) 352)
Hydrogenated rosin ester
30.0 parts by weight
Antioxidant 1.9 parts by weight
d-Limonene 3.0 parts by weight
______________________________________
Oxybutynin was added to the composition containing the above components so
as to have a content of oxybutynin of 0.1 weight part. The mixture was
heated up to 180.degree. C. under nitrogen gas flow, and mixed and
stirred. After stirring for two hours, the obtained mixture was applied
onto a release liner so as to have a thickness of 50 .mu.m to form a base
layer. Then the base layer thus obtained was laminated on a polyester film
(thickness: 25 .mu.m) to obtain a formulation for percutaneous
administration, for treating disturbance in micturition.
Example 27
______________________________________
High-molecular weight Polyisobutylene
0.5 parts by weight
(viscosity-average molecular weight: 2,300,000)
Low-molecular weight Polyisobutylene
9.0 parts by weight
(viscosity-average molecular weight: 50,000)
Styrene-isoprene-styrene Block copolymer
21.0 parts by weight
Liquid paraffin 36.0 parts by weight
(Crystol (Registered Trademark) 352)
Hydrogenated rosin ester
27.0 parts by weight
Antioxidant 1.5 parts by weight
______________________________________
Oxybutynin was added to the composition containing the above components so
as to have a content of oxybutynin of 5 weight part. The mixture was
heated up to 180.degree. C. under nitrogen gas flow, and mixed and
stirred. After stirring for two hours, the obtained mixture was applied
onto a release liner so as to have a thickness of 50 .mu.m to form a base
layer. Then the base layer thus obtained was laminated on a polyester film
(thickness: 25 .mu.m) to obtain a formulation for percutaneous
administration for treating disturbance in micturition.
Example 28
______________________________________
High-molecular weight Polyisobutylene
0.3 parts by weight
(viscosity-average molecular weight: 1,900,000)
Low-molecular weight Polyisobutylene
12.7 parts by weight
(viscosity-average molecular weight: 90,000)
Styrene-isoprene-styrene Block copolymer
24.0 parts by weight
Liquid paraffin 28.0 parts by weight
(Crystol (Registered Trademark) 352)
Hydrogenated rosin ester
30.0 parts by weight
Antioxidant 2.0 parts by weight
______________________________________
Oxybutynin was added to the composition containing the above components so
as to have a content of oxybutynin of 3 weight part. The mixture was
heated up to 180.degree. C. under nitrogen gas flow, and mixed and
stirred. After stirring for two hours, the obtained mixture was applied
onto a release liner so as to have a thickness of 50 .mu.m to form a base
layer. Then the base layer thus obtained was laminated on a polyester film
(thickness: 25 .mu.m) to obtain a formulation for percutaneous
administration for treating disturbance in micturition.
Comparative Example 1
______________________________________
Styrene-isoprene-styrene Block copolymer
18.0 parts by weight
Liquid paraffin 34.0 parts by weight
(Crystol (Registered Trademark) 352)
Hydrogenated rosin ester
34.0 parts by weight
HPE - 101(1-›2-(decylthio)ethyl!azacyclopentane-
3.0 parts by weight
2-one: generic name: pirotiodecane)
Antioxidant 1.0 parts by weight
______________________________________
A formulation for percutaneous administration for treating disturbance in
micturition in the same manner as described in Example 4, except that the
composition containing the above components.
Comparative Example 2
______________________________________
Gelatin 15.0 parts by weight
Nikasol TS - 620 5.0 parts by weight
(88% partial saponified) Polyvinyl alcohol
10.0 parts by weight
Glycerin 25.6 parts by weight
p-Oxy methyl benzoate
0.2 parts by weight
Aluminum glycinate 0.2 parts by weight
Purified water 40.0 parts by weight
Oxybutynin 4.0 parts by weight
______________________________________
In the purified water heated to 70.degree. C., the above gelatin, polyvinyl
alcohol and Nikasol TS-620 were dissolved sequently to obtain a solution
(I). Then, after dissolving p-oxy methyl benzoate and oxybutynin in
glycerin heated to 70.degree. C., a dispersion, in which maleic
anhydride-methyl vinyl ether block copolymer and aluminum glycinate were
dispersed homogeneously, was added to the above solution (I) and mixed.
Then the mixture thus obtained was applied on a release liner treated with
silicone to have a thickness of 300 .mu.m, and it was laminated on the
PET-treated surface of unwoven fabric, in which one surface had been
treated with PET, to obtain a cataplasm containing oxybutynin.
Comparative Example 3
______________________________________
2-Ethylhexyl acrylate
75.0 parts by weight
Methyl methacrylate
15.0 parts by weight
Acrylic acid 10.0 parts by weight
Azobisisobutyronitrile
0.02 parts by weight
______________________________________
The composition containing the above components was polymerized at
60.degree. C. for 48 hours in ethyl acetate/toluene (1/1) solvent so as to
have total solids of 40 weight %. To the obtained polymer solution, 0.1
parts by weight of isocyanate crosslinking agent and oxybutynin were added
so as to have a content of oxybutynin of 10 wt % when dried, and applied
onto a liner treated with silicone to have a thickness of 50 .mu.m, and
dried. Then the base layer thus obtained was laminated on a polyester film
(thickness: 25 .mu.m) to obtain an acrylic tape containing oxybutynin.
Comparative Example 4
______________________________________
Gelatin 3.0 parts by weight
Maleic anhydride - methyl vinyl ether copolymer
3.0 parts by weight
(GANTREZ 169)
Partial saponified polyvinyl alcohol
5.0 parts by weight
Sodium polyacrylate 2.0 parts by weight
Glycerin 31.0 parts by weight
p-Oxy methyl benzoate 0.2 parts by weight
Purified water 49.6 parts by weight
Oxybutynin 4.0 parts by weight
______________________________________
In the purified water heated to 70.degree. C., the above gelatin, sodium
polyacrylate, maleic anhydride-methyl vinyl ether copolymer were dissolved
sequently to obtain a solution (I). Then, after dissolving partial
saponified polyvinyl alcohol, p-oxy methyl benzoate and oxybutynin in
glycerin heated to 70.degree. C., it was added to the above solution (I)
and mixed. The mixture was applied on a release liner treated with
silicone to have a thickness of 300 .mu.m. Then it was laminated on the
PET-treated surface of unwoven fabric, in which one surface had been
treated with PET, to obtain a cataplasm containing oxybutynin.
Comparative Example 5
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 1
except that 32.0 parts by weight of high-molecular weight polyisobutylene
(viscosity-average molecular weight: 1,110,000) was used and that
low-molecular weight polyisobutylene was not used.
Comparative Example 6
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 1
except that 32.0 parts by weight of low-molecular weight polyisobutylene
(viscosity-average molecular weight: 40,000) was used and that
high-molecular weight polyisobutylene was not used.
Comparative Example 7
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 2
except that 43.0 parts by weight of high-molecular weight polyisobutylene
(viscosity-average molecular weight: 1,110,000) was used and that
low-molecular weight polyisobutylene was not used.
Comparative Example 8
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 2
except that 43.0 parts by weight of low-molecular weight polyisobutylene
(viscosity-average molecular weight: 40,000) was used and that
high-molecular weight polyisobutylene was not used.
Comparative Example 9
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 3
except that 47.0 parts by weight of high-molecular weight polyisobutylene
(viscosity-average molecular weight: 990,000) was used and that
low-molecular weight polyisobutylene was not used.
Comparative Example 10
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 3
except that 47.0 parts by weight of low-molecular weight polyisobutylene
(viscosity-average molecular weight: 30,000) was used and that
high-molecular weight polyisobutylene was not used.
Comparative Example 11
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 4
except that 9.0 parts by weight of high-molecular weight polyisobutylene
(viscosity-average molecular weight: 1,110,000) was used and that
low-molecular weight polyisobutylene was not used.
Comparative Example 12
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 4
except that 9.0 parts by weight of low-molecular weight polyisobutylene
(viscosity-average molecular weight: 40,000) was used and that
high-molecular weight polyisobutylene was not used.
Comparative Example 13
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 5
except that 8.0 parts by weight of high-molecular weight polyisobutylene
(viscosity-average molecular weight: 1,600,000) was used and that
low-molecular weight polyisobutylene was not used.
Comparative Example 14
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 5
except that 8.0 parts by weight of low-molecular weight polyisobutylene
(viscosity-average molecular weight: 30,000) was used and that
high-molecular weight polyisobutylene was not used.
Comparative Example 15
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 6
except that 12.8 parts by weight of high-molecular weight polyisobutylene
(viscosity-average molecular weight: 1,110,000) was used and that
low-molecular weight polyisobutylene was not used.
Comparative Example 16
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 6
except that 12.8 parts by weight of low-molecular weight polyisobutylene
(viscosity-average molecular weight: 40,000) was used and that
high-molecular weight polyisobutylene was not used.
Comparative Example 17
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 7
except that 12.1 parts by weight of high-molecular weight polyisobutylene
(viscosity-average molecular weight: 1,600,000) was used and that
low-molecular weight polyisobutylene was not used.
Comparative Example 18
A formulation for percutaneous administration for treating disturbance in
micturition was obtained in the same manner as described in Example 7
except that 12.1 parts by weight of low-molecular weight polyisobutylene
(viscosity-average molecular weight: 30,000) was used and that
high-molecular weight polyisobutylene was not used.
Comparative Example 19
(A Manufacture of formulation for percutaneous administration for treating
disturbance in micturition using the same composition and the same method
as described in Example 3 of the Japanese Un-Examined Patent Publication
No.Hei 4-273818)
______________________________________
Ethylhexyl acrylate 82.0 parts by weight
(manufactured by Rohmfahm, Germany)
Propylene glycol 8.0 parts by weight
Oxybutynin 10.0 parts by weight
______________________________________
A suspension of ethylhexyl acrylate (7927/80, manufactured by Rohmfahm) was
heated at 120.degree. C. for 30 min. to obtain an adhesive layer. After
cooling, oxybutynin dissolved in propylene glycol was mixed with it, to
have an adhesive for percutaneous absorption. The adhesive was applied on
the surface of paper treated with polyethylene, being a release liner, so
as to have a thickness of 50 .mu.m, to obtain a drug-containing layer of a
patch containing oxybutynin. Then, the drug-containing layer was laminated
on the treated surface of a porous polyethylene film, being a backing,
(pore diameter: approx.0.2 mm, distance between pores: 1.5 mm) in which
the surface had been oxidation-treated, so that the opposite surface of
the linear liner was contacted, to obtain a formulation for percutaneous
administration for treating disturbance in micturition containing
oxybutynin.
Comparative Example 20
(A Manufacture of formulation for percutaneous administration for treating
disturbance in micturition using the same composition and the same method
as described in Example 3 of the Japanese Un-Examined Patent Publication
No.Hei 4-99719)
______________________________________
Purified Water 31.5 parts by weight
Oleic acid 1.0 parts by weight
Glycerin 15.0 parts by weight
Butanediol 15.0 parts by weight
Sodium carboxymethylcellulose
9.0 parts by weight
Sodium polyacrylate
7.0 parts by weight
Gelatin 4.0 parts by weight
Kaolin 7.0 parts by weight
Citric acid 0.5 parts by weight
Oxybutynin hydrochloride
10.0 parts by weight
______________________________________
Oxybutynin hydrochloride was dissolved in water and it was mixed with the
above other components homogeneously to obtain a formulation for
percutaneous administration for treating disturbance in micturition
containing oxybutynin.
Test Example 1
(Test of stability against change with time)
In order to examine the stabilities against change with time of the
formulations obtained in Examples 1 to 7 and Comparative Examples 1 to 18,
a test of the remaining amounts of the medicines (Examples 1 to 7 and
Comparative Examples 1 to 4) during storage, and of the changes with time
of the physical characteristics of the formulations (Examples 1 to 7 and
Comparative Examples 1 to 18) were made. The storage condition of each
formulation was to seal it in an aluminum package at 40.degree. C. The
remaining amount of oxybutynin in each formulation was determined with
HPLC method.
In addition, as the physical characteristics, observations on the
adhesiveness and appearance were carried out. The adhesiveness was
determined by observing the changes with time of the adhesive property
(probe tack value (g/cm.sup.2) using a probe tack tester (manufactured by
Rigaku Kogyo kk). The appearance was evaluated in accordance with the
following standards. The results are shown in the Tables 1 and 2.
TABLE 1
__________________________________________________________________________
Changes with time of remaining amount of Oxybutynin (wt %)
Example No. Comp. Example No.
1 2 3 4 5 6 7 1 2 3 4
__________________________________________________________________________
1 months
99.9
99.9
99.7
99.8
99.9
99.9
99.8
99.5
98.4
99.5
99.0
2 months
99.7
99.1
99.5
99.8
99.2
99.7
99.5
99.1
96.3
97.5
85.6
3 months
99.1
98.3
99.1
99.8
98.5
99.3
99.2
98.9
91.0
93.5
78.6
6 months
98.6
98.4
98.9
99.5
97.9
98.7
98.4
98.6
84.1
88.6
68.3
__________________________________________________________________________
TABLE 2
______________________________________
Changes with time of physical characteristics of formulations
______________________________________
Example No.
1 2 3 4 5 6 7
______________________________________
Initial
Prove tack
211 209 211 212 237 310 305
Appearance
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
1 month
Prove tack
200 207 210 222 226 308 303
Appearance
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
months
Prove tack
205 195 208 220 226 307 301
Appearance
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
3
months
Prove tack
198 203 205 219 220 305 301
Appearance
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
6
months
Prove tack
208 195 204 215 210 301 298
Appearance
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
______________________________________
Comparative Example No.
1 2 3 4 5 6 7 8 9
______________________________________
Initial
Prove 450 50 305 34 99 230 101 242 98
tack
Appear-
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
ance
1 month
Prove 420 49 303 32 98 232 98 240 96
tack
Appear-
.circleincircle.
.largecircle.
.circleincircle.
.largecircle.
.circleincircle.
X .circleincircle.
X .circleincircle.
ance
months
Prove 400 40 306 30 95 240 101 236 97
tack
Appear-
.circleincircle.
.DELTA.
.circleincircle.
.DELTA.
.circleincircle.
X .circleincircle.
X .circleincircle.
ance
3
months
Prove 400 32 301 29 97 242 97 243 91
tack
Appear-
.circleincircle.
.DELTA.
.largecircle.
.DELTA.
.circleincircle.
X .circleincircle.
X .circleincircle.
ance
6
months
Prove 398 -- 300 25 95 245 98 241 93
tack
Appear-
.circleincircle.
X .DELTA.
X .circleincircle.
X .circleincircle.
X .circleincircle.
ance
______________________________________
Comparative Example No.
10 11 12 13 14 15 16 17 18
______________________________________
Initial
Prove 235 108 245 110 252 152 358 161 382
tack
Appear-
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
.circleincircle.
ance
1 month
Prove 248 105 246 105 251 154 352 160 386
tack
Appear-
X .circleincircle.
X .circleincircle.
X .circleincircle.
X .circleincircle.
X
ance
months
Prove 240 102 250 105 248 150 351 158 390
tack
Appear-
X .circleincircle.
X .circleincircle.
X .circleincircle.
X .circleincircle.
X
ance
3
months
Prove 245 108 252 107 250 155 360 157 395
tack
Appear-
X .circleincircle.
X .circleincircle.
X .circleincircle.
X .circleincircle.
X
ance
6
months
Prove 242 103 260 108 251 152 355 155 397
tack
Appear-
X .circleincircle.
X .circleincircle.
X .circleincircle.
X .circleincircle.
X
ance
______________________________________
Probe tack value: (g/cm.sup.2)
.circleincircle.: unchanged
.largecircle.: some decrease in viscosity
.DELTA.: some exudation
X: exudation and stringing
As it is apparent from the results shown in Table 1, the remaining amounts
of oxybutynin in formulations for percutaneous administration for treating
disturbance in micturition of the present invention, were scarcely changed
and were stable, while the remaining amounts of oxybutynin in the
formulations of Comparative Examples were extremely decreased with time
and the stability was poor, except Comparative Example 1.
In addition, as it is apparent from the results shown in Table 2, all of
the formulations for percutaneous administration for treating disturbance
in micturition of Examples of the present invention, exhibited sufficient
physical stabilities, while in the formulations of Comparative Examples,
the physical stabilities were extremely poor and thus it was proved that
the commercialization of the formulations of Comparative Examples was
impossible.
Moreover, each formulation for percutaneous administration for treating
disturbance in micturition obtained in Examples 8 to 28, showed the same
stabilities with time as each formulation for percutaneous administration
for treating disturbance in micturition of Examples 1 to 7.
Test Example 2
(Test of irritativenss to skin)
In order to examine the irritativeness to skin of each formulation obtained
in Examples 1 to 7 and Comparative Examples 1 to 4, patch test (applied
for 48 hours) was carried out on healthy men. The results were shown in
the following Table 3.
TABLE 3
__________________________________________________________________________
Results of the test of irritativenss to skin
Examples Comp. Example
1 2 3 4 5 6 7 1 2 3 4
__________________________________________________________________________
SI value
10.3
7.8
9.4
13.0
14.6
7.8
9.2
24.8
30.5
45.4
21.3
__________________________________________________________________________
SI value: skin irritation index
From the results shown in Table 3, the formulation for percutaneous
administration for treating urinary incontinence of the present invention
obtained in Examples 1 to 7, were low irritative, while the formulations
of Comparative Examples 1 to 4 were high irritative and thus it was
apparent that the performances as formulations for percutaneous
administration were inferior.
Test Example 3
(Test of transdermal absorption using rats)
The in vivo transdermal absorbability of each formulation obtained in
Examples 1 to 7 and Comparative Examples 1 to 4, 19 and 20 was examined
using rats. Each formulation formed into a circular shape having a
diameter of 2 cm, was applied onto abdomen of depilated rat, and the
change with time of blood concentration was determined with gas
chromatography. The results were shown in FIG. 1. From the results shown
in FIG. 1, the formulations for percutaneous administration for treating
disturbance in micturition of the present invention obtained in Examples 1
to 7, apparently had excellent transdermal absorbabilities compared with
each formulation of Comparative Examples 1 to 4, 19 and 20.
Test Example 4
(Test of transdermal absorption using human skin)
An investigation on in vitro transdermal absorbability of each formulation
obtained in Examples 1 to 7 and Comparative Examples 1 to, 4, 19 and 20
using cadaver skin, was made.
Each formulation formed into a circular shape having a diameter of 3 cm,
was applied onto cadaver skin, and then it was set to a flow cell
connected to a fraction connecter to determine the drug permeation amounts
with time using gas chromatography. The results are shown in FIG. 2. From
the results shown in FIG. 2, it was apparent that the formulations for
percutaneous administration for treating disturbance in micturition of the
present invention obtained in Examples 1 to 7 had more excellent
transdermal absorbabilities compared with the formulations of Comparative
Examples 1 to 4, 19 and 20.
Test Example 5
(Evaluation test of pharmaceutical effects with cystometry using rats)
The abdominal part of a rat was incised medianly under urethane anesthesia,
a catheter having two cavities was inserted into the cupular part of the
bladder. The one catheter was connected to a transducer for the
measurement of internal pressure of the bladder, and the other catheter
was connected to a pump for continuous injection. When saline warmed to
37.degree. C. was injected into the bladder at a rate of 46 .mu.l/min, a
temporary micturition contraction accompanied with micturition was
observed after few minutes. At that time, the volume of saline injected
until micturition was occurred was regarded as the threshold volume of
micturition (VT), the internal pressure of the bladder just before the
micturition was regarded as the threshold pressure of micturition (PT),
and the maximum internal, pressure at the time of the micturition
contraction was regarded as the maximum pressure of micturition
(P.sub.max). The pharmacological actions of the formulations for
percutaneous administration for treating disturbance in micturition of the
present invention in relation to the three parameters were examined.
The tests were carried out, by applying 2cm.sup.2 of the formulation for
percutaneous administration for treating disturbance in micturition of the
present invention obtained in the above Example 4 to the chest of a rat.
The results were shown in FIG. 3.
As shown in FIG. 3, in the formulation for percutaneous administration of
the present invention, the threshold volume of micturition (VT) increased
significantly even after 24 hours from the application, compared with the
non-treated group. The larger the threshold volume of micturition (VT),
the larger the accumulated amount of urine and the longer the interval of
micturition. It can be considered that the increase of the threshold
volume of micturition (VT) by applying the formulation for percutaneous
administration of the present invention, was due to the synergistic effect
of the relaxing action on bladder smooth muscle and the anticholinergic
action of oxybutynin which is the medicine for treating disturbance in
micturition contained in the formulation.
In addition, the change of the threshold pressure of micturition (PT) was
not observed compared with the non-treated group, but the maximum pressure
of micturition (P.sub.max) decreased significantly. It can be supposed
that the significant decrease of the maximum pressure of micturition
(P.sub.max) was due to the anticholinergic action of oxybutynin which is a
medicine for treating disturbance in micturition contained in the
formulation of the present invention.
From the results of the above test, it was proved that the formulation for
percutaneous administration for treating disturbance in micturition of the
present invention, showed excellent and continuing pharmaceutical effects.
Industrial Applicability
The formulation for percutaneous administration for treating disturbance in
micturition of the present invention is excellent in stability against
change with time, low irritative to skin, and excellent in transdermal
absorbability, by using the above base components. Further, since the
contained medicine for treating disturbance in micturition is released
continuously directly in the circulating blood via skin, the medicine is
not metabolized due to the fast-pass effect occurred in liver at the time
of oral administration, and the side-effects due to the temporary increase
in the concentrations in blood are not occurred. In addition, the
bioavailability of the medicine for treating disturbance in micturition is
increased, and the medicine can be administered in the bodies efficiently.
Further, by containing a transdermal absorption enhancer if desired, a more
sufficient transdermal absorbability may be attained, and an excellent
effect may be exhibited.
Moreover, since the number of times of administration (a number of times of
administration per unit hours) may be small using the formulation for
percutaneous administration for treating disturbance in micturition of the
present invention, the damages given to skin may be controlled at a
minimum.
Top